CN106822921A - A kind of nanometer medicine-carried system and its preparation and application - Google Patents
A kind of nanometer medicine-carried system and its preparation and application Download PDFInfo
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- CN106822921A CN106822921A CN201611270207.6A CN201611270207A CN106822921A CN 106822921 A CN106822921 A CN 106822921A CN 201611270207 A CN201611270207 A CN 201611270207A CN 106822921 A CN106822921 A CN 106822921A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
Abstract
The present invention relates to pharmaceutical technology field, there is provided a kind of nanometer medicine-carried system, including：Magnetic mesoporous silicon dioxide nano rod carrier, load pro-drug GCV on this carrier, and the graft copolymer PLLgPEG formed by many PLLs and polyethylene glycol, wherein, PLLgPEG has been also loaded suicide gene TK.Using magnetic mesoporous silicon dioxide nano rod as magnetic targeted carrier, load suicide gene TK/ pro-drugs GCV enters cell, suicide gene and pro-drug transmission uniformity temporally and spatially is realized, accurately to release the drug.Effectively combined by magnetic mesoporous silicon dioxide nano rod and suicide gene/prodrugs therapy method, and then improve the combined therapy effect of liver cancer.The preparation method of the nanometer medicine-carried system that the present invention is provided, process is simple is adapted to large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of nanometer medicine-carried system and its preparation and application.
Background technology
Liver cancer is to threaten one of disease the most serious to human health at present, is to be only second to stomach cancer, the 3rd of cancer of the esophagus the
Big common cancer, China dies from the people of liver cancer patient about 110,000, accounts for the 45% of whole world PLC mortality number every year.Liver cancer is controlled
Treating conventional method includes operative treatment, chemotherapy and radiation, wherein, chemotherapy is the means for the treatment of cancer most potentiality to be exploited and grinds
Study carefully one of direction.With the progress on the increasing of effective chemotherapeutics, therapeutic strategy, status of the chemotherapy in liver cancer complex treatment
Increasingly improve, proportion increasingly increases.
However, clinically the early diagnosis of liver cancer is difficult at present, and most chemotherapeutics lack targeting, while also existing
Larger toxic and side effect, serious influence is caused to the healthy of patient.Therefore, how cancer therapy drug targeting to be transported to
Tumor locus, reduce intake of the normal structure to medicine, so as to reduce its side effect, improve the curative effect of medicine, are current chemotherapeutics
The research emphasis and difficult point of medicine.
Gene therapy is the most potential new technology of 21 century treatment liver cancer, wherein, suicide gene/pro-drug system is controlled
Treatment is the treatment method for growing up last century end.As conventional suicide gene system, herpes simplex virus thymidine kinase/the third
Oxygen guanosine (HSV-TK/GCV) system is mainly by the way of KT genes and pro-drug GCV Synergistic treatments.Import tumor tissues
In TK gene codified thymidine kinases, the non-toxic pro-drug that will be given is transformed into toxicant, so as to kill cell.To the greatest extent
Pipe suicide gene/pro-drug system therapy development is very rapid, but because it has precursor medicine in city-level clinical practice
It is short to there is blood halflife in inconsistency, suicide gene body in the passing time and space of thing and suicide gene, gene transfection efficiency
Relatively low, cancer target identity is poor, the low shortcomings of monotherapy efficiency, seriously limit its clinically further should
With.
Magnetic nano drug delivery system is a kind of compound target drug-delivery system that developed recently gets up, the system
By that can be constituted as the magnetic nano-particle of NMR imaging contrast agent and as the mesoporous silicon oxide of pharmaceutical carrier, because it is unique
Property be successfully used in tumor diagnosis and therapy.Janus types magnetic-mesoporous silicon dioxide nano particle (Fe3O4-mSiO2) many
Function and service carrier not only has good biocompatibility, relatively low cytotoxicity and saturation magnetization higher, can be with
Magnetic targeted conveying medicine is carried out, and gene can simultaneously be carried based on its special structure and small-molecule drug enters cell, tool
For the possibility of accurate drug release over time and space.Additionally, Janus types magnetic-mesoporous silicon dioxide nano particle also has very
Good magnetic heat cure effect.
Therefore, Chinese patent literature CN105079825A discloses a kind of nano-particle, including meso-porous titanium dioxide silicon rod, it is embedding
It is located at the magnetic particle of described silica bar one end, and the antibody for being supported on the silica bar surface.The invention institute
The nano-particle stated causes skin effect, and surface antibody can be specific with the mating with surface antigen, improves it
Antibacterial ability, additionally, the nano-particle has excellent magnetic ability concurrently, can realize the separation of bacterium.Meanwhile, the nano-particle
Have magnetic and biocompatibility concurrently, the application in biomedical imaging can be realized.
Therefore, how by Fe3O4-mSiO2Multifunctional nanoparticle carrier and altogether load suicide gene/pro-drug combination, open
Hair good biocompatibility, magnetic target tropism are strong, suicide gene/pro-drug cooperates with release, various method therapeutic alliances in cell
Multifunctional nano medicine-carried system, and then realize the complex treatment of liver cancer high-efficiency low-toxicity, be current technical problem urgently to be resolved hurrily.
The content of the invention
Therefore, the technical problems to be solved by the invention be existing suicide gene/pro-drug system therapy in space and
The inconsistency of insoluble drug release, targets identification be poor on time, poor biocompatibility, monotherapy efficiency are low, and then provides one
Kind of good biocompatibility, targeting are strong, suicide gene/pro-drug cooperates with release in cell, various method therapeutic alliances
Multifunctional nano medicine-carried system.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
Nanometer medicine-carried system of the present invention, including：Magnetic-mesoporous silicon dioxide nano rod carrier, is supported on the load
Prodrug ganciclovir (gancyclovir, abbreviation GCV) on body, and by poly-l-lysine (PLL) and polyethylene glycol
(PEG) the graft copolymer PLL-g-PEG for being formed, wherein, the PLL-g-PEG has been also loaded suicide gene herpes simplex virus
Thymidine kinase (herpes simplex virus thymidine kinase, abbreviation HSV-TK, TK).
Optionally, the magnetic-mesoporous silicon dioxide nano rod carrier is embedded with the meso-porous titanium dioxide of magnetic particle for one end
Silicon nanorod.
Optionally, the length of the mesoporous silicon dioxide nano rod is 20-500nm, and a diameter of 70-150nm, aperture is 1-
5nm；The particle diameter of the magnetic particle is 50-150nm, and specific surface area is 400-1200m2/ g, accumulative pore volume is not less than
0.5cm3/g；The magnetic-mesoporous silicon dioxide nano rod carrier magnetic response ability is not less than 57emu/g；The meso-porous titanium dioxide
The GCV load capacity of silicon nanorod is 5-40%；The suicide gene TK load capacity is 5-20%.
Optionally, the magnetic particle is r-Fe2O3、MeFe2O3、Fe3O4, in MnO, NiO, NiFe, FeCo, NiFe extremely
Few one kind, wherein, Me is the one kind in Co, Mn, Ni.
Also a kind of method for preparing described nanometer medicine-carried system of the present invention, comprises the following steps：
(1) functionalization of magnetic-mesoporous silicon dioxide nano rod carrier
Magnetic-mesoporous silicon dioxide nano rod carrier is dissolved in alcohol solvent, silane coupler is added after ultrasonic disperse, instead
Answer and flow back at a temperature of 105 DEG C of liquid 4h, separate, washing, dry, prepare amidized magnetic-mesoporous silicon dioxide nano rod and carry
Body；Amidized magnetic-mesoporous silicon dioxide nano rod the carrier is added in the succinic anhydride solution of 10-50mg/ml, 25
DEG C stirring 24h, product through Magnetic Isolation, washing, be prepared into carboxylated carrier；
(2) carrying precursor medicine GCV
The carboxylated carrier prepared by the step (1) is dissolved in the cushioning liquid of pro-drug GCV, stirring is incubated
24h is educated, magnetic is isolated and purified, be prepared into the carrier of carrying precursor medicine GCV；
(3) PLL-g-PEG is prepared
Poly-l-lysine PLL is carried out into NHS/EDC reactions with polyethylene glycol PEG in molar ratio for mix at 1: 1, is reacted
25 DEG C of temperature, reaction time 6h forms graft copolymer PLL-g-PEG；
(4) carrier cladding PLL-g-PEG
By the carrier and PLL-g- obtained in the step (3) of the carrying precursor medicine GCV obtained in the step (2)
PEG (1.5-2.5) in mass ratio: 1 mixes in physiological conditions, the reaction time is 18-32h, and reaction solution is through centrifugation, washing, true
Sky is dried, and the carrier of cladding PLL-g-PEG is obtained；
(5) TK plasmids are loaded
The carrier of the cladding PLL-g-PEG obtained in the step (4) is pressed into matter with the plasmid of the suicide gene TK
Amount than (5-15): 1 in physiological conditions stirring reaction 18-32h be combined, reaction solution through centrifugation, washing, be obtained nano drug-carrying
System, i.e. Fe3O4-mSiO2/GCV@PLL-g-PEG/TK。
Optionally, the poly-l-lysine molecular weight is 70000-150000, and the molecular weight polyethylene glycol is 1000-
100000。
Optionally, the step (4) and the physiological condition described in the step (5) are PBS, and pH value is 6.8-
7.2, temperature is 20-25 DEG C.
Optionally, a kind of preparation method of described nanometer medicine-carried system, further comprising the steps of：
Prepare magnetic particle
By the 30-40 DEG C of stirring under nitrogen protection of the mixture of magnetic presoma, polyacrylic acid PAA and diethylene glycol (DEG) DEG
30 minutes, 100~1000rpm of speed of agitator was heated to 240~280 DEG C afterwards, continues 100~1000rpm and stirs 30 minutes,
The first reaction solution is obtained；
The diethylene glycol (DEG) DEG solution of the NaOH of 60~75 DEG C of injection in first reaction solution, continuation 100~
1000rpm is stirred 1 hour and reacted, and generates magnetic particle；
The magnetic particle is separated, is washed, being dried；
Prepare magnetic-mesoporous silicon dioxide nano rod carrier
1ml concentration is added to the water of 5-10mg/ml surfactants for the magnetic particle aqueous solution of 8.6mg/ml
It is fully dispersed in solution, alkalescent reagent is added, continue to stir 30 minutes after tetraethyl orthosilicate is slowly added to afterwards, wash away institute
Surfactant is stated, the magnetic-mesoporous silicon dioxide nano rod carrier is obtained.
Optionally, the magnetic presoma is the one kind in soluble ferric iron salt, manganese salt, nickel salt；The polyacrylic acid molecule
It is 1800-15000 to measure；The surfactant is the one kind or many in alkyl quaternary ammonium salts, polyvinylpyrrolidone, polyethyene diamine
Kind.
The present invention is also provided includes a kind of drug regimen of above-mentioned nanometer medicine-carried system and the auxiliary material for pharmaceutically receiving
Thing.
Technical solution of the present invention, has the following advantages that：
1. a kind of nanometer medicine-carried system provided in an embodiment of the present invention, using with good biocompatibility, relatively low cell
Toxicity, compared with high saturation and magnetic intensity magnetic-mesoporous silicon dioxide nano rod as carrier, load suicide gene TK/ pro-drugs
GCV, based on magnetic-mesoporous silicon dioxide nano rod special construction, can simultaneously carry suicide gene and pro-drug small molecule enters
Cell, realizes suicide gene and pro-drug transmission uniformity temporally and spatially accurately to release the drug, and, magnetic-
Mesoporous silicon dioxide nano rod also has good magnetic heat cure effect.By magnetic-mesoporous silicon dioxide nano rod and suicide base
Cause/prodrugs therapy method is effectively combined, and then improves the combined therapy effect of liver cancer.
2. a kind of preparation method of nanometer medicine-carried system provided in an embodiment of the present invention, process is simple, are adapted to large-scale
Industrial production.
Brief description of the drawings
In order to illustrate more clearly of the specific embodiment of the invention or technical scheme of the prior art, below will be to specific
The accompanying drawing to be used needed for implementation method or description of the prior art is briefly described, it should be apparent that, in describing below
Accompanying drawing is some embodiments of the present invention, for those of ordinary skill in the art, before creative work is not paid
Put, other accompanying drawings can also be obtained according to these accompanying drawings.
Fig. 1 is the transmission electron microscope picture of nanometer medicine-carried system magnetic-mesoporous silicon dioxide nano rod；
Wherein, reference is expressed as in Fig. 1：11 is magnetic particle, and 12 is mesoporous silicon dioxide nano rod.
Fig. 2 is the nitrogen adsorption-desorption curve of the magnetic-mesoporous silicon dioxide nano rod of nanometer medicine-carried system.
Fig. 3 is the hysteresis curve of the magnetic-mesoporous silicon dioxide nano rod of nanometer medicine-carried system.
Fig. 4 is the tablets in vitro figure of the magnetic-mesoporous silicon dioxide nano rod of nanometer medicine-carried system.
Fig. 5 kills figure for the cellular level HCC of the magnetic-mesoporous silicon dioxide nano rod of nanometer medicine-carried system.
Fig. 6 is the tumor suppression figure of the magnetic-mesoporous silicon dioxide nano rod of nanometer medicine-carried system.
Fig. 7 is the nuclear-magnetism of magnetic-mesoporous silicon dioxide nano rod that nanometer medicine-carried system carries pro-drug and suicide gene altogether
Image.
Specific embodiment
Technical scheme is clearly and completely described below in conjunction with accompanying drawing, it is clear that described implementation
Example is a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, ordinary skill
The every other embodiment that personnel are obtained under the premise of creative work is not made, belongs to the scope of protection of the invention.
As long as additionally, technical characteristic involved in invention described below different embodiments does not constitute conflict just each other
Can be combined with each other.
It should be appreciated that the suicide gene TK described in this patent document refers to herpes simplex virus thymidine kinase (English
Literary fame claims herpes simplex virus thymidine kinase, abbreviation HSV-TK, TK), pro-drug GCV is the third oxygen
Guanosine (English name gancyclovir, abbreviation GCV).
The reagent being related in following embodiments is commercially available prod, and the reagent of different manufacturers and model is for result not
Obvious difference can be brought.
Embodiment 1
The present embodiment provides a kind of nanometer medicine-carried system, as shown in figure 1, with magnetic-mesoporous silicon dioxide nano rod as carrier
1, carrying precursor medicine GCV on the carrier 1, and be total to by the grafting that poly-l-lysine (PLL), polyethylene glycol (PEG) are formed
Polymers PLL-g-PEG, wherein, PLL-g-PEG has been also loaded suicide gene TK, the magnetic-mesoporous silicon dioxide nano rod carrier 1 by
The magnetic particle 11 that mesoporous silicon dioxide nano rod 12 and its one end are embedded is constituted.
The length of mesoporous silicon dioxide nano rod 12 is 400nm, its a diameter of 100nm, and aperture is 2.8nm；Magnetic particle
11 materials are Fe3O4, its particle diameter is 80nm, and specific surface area is 650m2/ g, accumulation pore volume is 0.9cm3/g.Magnetic-mesoporous dioxy
The magnetic response ability of SiClx nanometer rods carrier 1 is 90emu/g；Mesoporous silicon dioxide nano rod 12 loads GCV, and load capacity is 25%；
Suicide gene TK load capacity is 10%.
The present embodiment also provides a kind of preparation method of nanometer medicine-carried system, comprises the following steps：
S1. magnetic particle is prepared
By magnetic presoma FeCl30.13g, polyacrylic acid PAA (9000) 0.576g, diethylene glycol (DEG) DEG 34ml, in nitrogen
Under protection, 30min, rotating speed 550rpm are stirred at 37 DEG C, be then heated to 260 DEG C and continue to stir 30min, rotating speed 550rpm, system
Obtain the first reaction solution；
The diethylene glycol solution 3.8ml of 67.5 DEG C of NaOH (20wt%) is injected in the first reaction solution, continues to stir anti-
Should, rotating speed is 550rpm, and the reaction time is 1h, is then separated, washed, dried, and obtains magnetic particle 11；
S2. magnetic-mesoporous silicon dioxide nano rod carrier is prepared
Magnetic particle obtained in step S1 is configured to the aqueous solution of 8.6mg/ml, the addition of the 1ml magnetic particles aqueous solution is taken
It is fully dispersed in the aqueous solution (5mg/ml, 10ml) containing surfactant cetyl trimethylammonium bromide, add alkalescent
Reagent ammoniacal liquor (25%-28%) 500ml, is then slowly added into tetraethyl orthosilicate 0.03ml, stirs 30min, is washed away using ethanol
Surfactant, is obtained magnetic-mesoporous silicon dioxide nano rod carrier 1；
S3. the functionalization of magnetic-mesoporous silicon dioxide nano rod carrier
Magnetic obtained in step S2-mesoporous silicon dioxide nano rod carrier 1 is dissolved in 10ml ethanol, is added after ultrasonic disperse
Silane coupler 1ml, flow back 4h at a temperature of 105 DEG C of reaction solution, separates, washing, dries, and prepares amidized magnetic-mesoporous
Silicon dioxide nano rod carrier；The ethanol that amidized magnetic-mesoporous silicon dioxide nano rod carrier is added into succinic anhydride is molten
Liquid (50mg/ml, 10ml), 25 DEG C of stirring 24h, product is prepared into carboxylated carrier, i.e. Fe through Magnetic Isolation, washing3O4-
mSiO2-COOH；
S4. carrying precursor medicine GCV
Carboxylated carrier obtained in step S3 is dissolved in the cushioning liquid PBS (10mg/ml, 10ml) of pro-drug GCV
In, stirring is incubated 24h, and magnetic is isolated and purified, and is prepared into the carrier of carrying precursor medicine GCV, i.e. Fe3O4-mSiO2/GCV；
S5. PLL-g-PEG is prepared
Poly-l-lysine PLL (110000) is entered with polyethylene glycol PEG (4000) in molar ratio for 1: 1 amount mixes
Row NHS/EDC reacts, 25 DEG C of reaction temperature, reaction time 6h, forms graft copolymer PLL-g-PEG；
S6. carrier coats PLL-g-PEG
By the carrier of carrying precursor medicine GCV and PLL-g-PEG in mass ratio 2: 1 obtained in step S5 obtained in step S4
Mixing, addition PBS, pH=7.0,23 DEG C of reaction temperature, the reaction time is 24h, and reaction solution is through centrifugation, washing, vacuum
Dry, the carrier of cladding PLL-g-PEG, i.e. Fe is obtained3O4-mSiO2/GCV@PLL-g-PEG；
S7. TK plasmids are loaded
The carrier of PLL-g-PEG will be coated obtained in S6 with the plasmid of suicide gene TK according to mass ratio 10: 1, PBS is added
Buffer solution, pH=7.0,23 DEG C of reaction temperature reacts 24h, and reaction solution is obtained complex treatment liver-cancer medicine, i.e., through centrifugation, washing
Fe3O4-mSiO2/GCV@PLL-g-PEG/TK。
Embodiment 2
The present embodiment provides a kind of nanometer medicine-carried system, with magnetic-mesoporous silicon dioxide nano rod as carrier, is born on carrier
Pro-drug GCV, and the graft copolymer PLL-g-PEG formed by poly-l-lysine (PLL), polyethylene glycol (PEG) are carried,
Wherein, PLL-g-PEG has been also loaded suicide gene TK, and the magnetic-mesoporous silicon dioxide nano rod carrier is received by mesoporous silicon oxide
The magnetic particle composition that rice rod and its one end are embedded.
The length of mesoporous silicon dioxide nano rod is 20nm, its a diameter of 70nm, and aperture is 1nm；Magnetic particle material is
r-Fe3O4, its particle diameter is 50nm, and specific surface area is 400m2/ g, accumulation pore volume is 0.5cm3/g.Magnetic-mesoporous silicon oxide is received
Rice rod carrier magnetic response ability is 57emu/g；Mesoporous silicon dioxide nano rod loads GCV, and load capacity is 5%；The suicide base
Because TK load capacity is 5%.
The present embodiment also provides a kind of preparation method of nanometer medicine-carried system, comprises the following steps：
S1. magnetic particle is prepared
By magnetic presoma FeCl30.21g, polyacrylic acid PAA (1800) 0.8g, diethylene glycol (DEG) DEG50ml, protect in nitrogen
Under shield, 30min, rotating speed 100rpm are stirred at 30 DEG C, be then heated to 240 DEG C and continue to stir 30min, rotating speed 100rpm, be obtained
First reaction solution；
The diethylene glycol solution 4ml of 60 DEG C of NaOH (10wt%) is injected in the first reaction solution, continues stirring reaction, turned
Speed is 100rpm, and the reaction time is 1h, is then separated, washed, dried, and obtains magnetic particle；
S2. magnetic-mesoporous silicon dioxide nano rod carrier is prepared
Magnetic particle obtained in step S1 is configured to the aqueous solution of 8.6mg/ml, the addition of the 1ml magnetic particles aqueous solution is taken
It is fully dispersed in the aqueous solution containing surfactant polyvinylpyrrolidone (10mg/ml, 15m1), add alkalescent reagent
Ammoniacal liquor (25%-28%) 300ml, is then slowly added into tetraethyl orthosilicate 0.015ml, stirs 30min, and surface is washed away using ethanol
Activating agent, is obtained magnetic-mesoporous silicon dioxide nano rod carrier；
S3. the functionalization of magnetic-mesoporous silicon dioxide nano rod carrier
Magnetic obtained in step S2-mesoporous silicon dioxide nano rod carrier is dissolved in 15ml ethanol, is added after ultrasonic disperse
Silane coupler 1ml, flow back 4h at 105 DEG C of reaction solution, separates, washs, dries, and prepares amidized magnetic-mesoporous dioxy
SiClx nanometer rods carrier；Amidized magnetic-mesoporous silicon dioxide nano rod carrier is added in the ethanol solution of succinic anhydride
(10mg/ml, 30ml), 25 DEG C of stirring 24h, product is prepared into carboxylated carrier, i.e. Fe through Magnetic Isolation, washing3O4-
mSiO2-COOH；
S4. carrying precursor medicine GCV
Carboxylated carrier obtained in step S3 is dissolved in the cushioning liquid PBS (10mg/ml, 10ml) of pro-drug GCV
In, stirring is incubated 24h, and magnetic is isolated and purified, and is prepared into the carrier Fe of carrying precursor medicine GCV3O4-mSiO2/GCV；
S5. PLL-g-PEG is prepared
Poly-l-lysine PLL (70000) is carried out with polyethylene glycol PEG (1000) in molar ratio for 1: 1 amount mixes
NHS/EDC reacts, 25 DEG C of reaction temperature, reaction time 6h, forms graft copolymer PLL-g-PEG；
S6. carrier coats PLL-g-PEG
By the carrier of carrying precursor medicine GCV and PLL-g-PEG in mass ratio 1.5 obtained in step S5 obtained in step S4
: 1 mixing, addition PBS, pH=6.8,20 DEG C of reaction temperature, reaction time 18h, reaction solution is through centrifugation, washing, vacuum
Dry, the carrier of cladding PLL-g-PEG, i.e. Fe is obtained3O4-mSiO2/GCV@PLL-g-PEG；
S7. TK plasmids are loaded
The carrier of PLL-g-PEG will be coated obtained in S6 with the plasmid of suicide gene TK according to mass ratio 5: 1, PBS is added
Buffer solution, pH=6.8,20 DEG C of reaction temperature, reaction time 18h, reaction solution is obtained complex treatment liver cancer medicine through centrifugation, washing
Thing, i.e. r-Fe2O3-mSiO2/GCV@PLL-g-PEG/TK。
Embodiment 3
The present embodiment provides a kind of nanometer medicine-carried system, with magnetic-mesoporous silicon dioxide nano rod as carrier, is born on carrier
Pro-drug GCV, and the graft copolymer PLL-g-PEG formed by poly-l-lysine (PLL), polyethylene glycol (PEG) are carried,
Wherein, PLL-g-PEG has been also loaded suicide gene TK, and the magnetic-mesoporous silicon dioxide nano rod carrier is received by mesoporous silicon oxide
The magnetic particle composition that rice rod and its one end are embedded.
The length of mesoporous silicon dioxide nano rod is 500nm, its a diameter of 150mm, and aperture is 5nm；Magnetic particle material
It is MnFe3O4, its particle diameter is 150mm, and specific surface area is 1200m2/ g, accumulation pore volume is 1.5cm3/g.Magnetic-meso-porous titanium dioxide
Silicon nanorod carrier magnetic response ability is 60emu/g；Mesoporous silicon dioxide nano rod loads GCV, and load capacity is 40%；It is described from
It is 20% to kill gene TK load capacity.
The present embodiment also provides a kind of preparation method of nanometer medicine-carried system, comprises the following steps：
S1. magnetic particle is prepared
By magnetic presoma FeCl30.15g, polyacrylic acid PAA (15000) 0.6g, diethylene glycol (DEG) DEG 50ml, in nitrogen
Under protection, 30min, rotating speed 1000rpm are stirred at 40 DEG C, are then heated to 280 DEG C and continue to stir 30min, rotating speed 1000rpm,
The first reaction solution is obtained；
The diethylene glycol solution 5ml of 75 DEG C of NaOH (10wt%) is injected in the first reaction solution, continues stirring reaction, turned
Speed is 1000rpm, and the reaction time is 1h, obtains magnetic particle；
S2. magnetic-mesoporous silicon dioxide nano rod carrier is prepared
Magnetic particle obtained in step S1 is configured to the aqueous solution of 8.6mg/ml, the addition of the 1ml magnetic particles aqueous solution is taken
It is fully dispersed in the aqueous solution (7.5mg/ml, 10ml) containing surfactant polyethyene diamine, add alkalescent reagent ammoniacal liquor
(25%-28%) 400ml, is then slowly added into tetraethyl orthosilicate 0.025ml, stirs 30min, and surface-active is washed away using ethanol
Agent, is obtained magnetic-mesoporous silicon dioxide nano rod carrier；
S3. the functionalization of magnetic-mesoporous silicon dioxide nano rod carrier
Magnetic obtained in step S2-mesoporous silicon dioxide nano rod carrier is dissolved in 20ml ethanol, is added after ultrasonic disperse
Silane coupler 2ml, flow back 4h at 105 DEG C of reaction solution, separates, washs, dries, and prepares amidized magnetic-mesoporous dioxy
SiClx nanometer rods carrier；Amidized magnetic-mesoporous silicon dioxide nano rod carrier is added in the ethanol solution of succinic anhydride
(30mg/ml, 15ml), 25 DEG C of stirring 24h, product is prepared into carboxylated carrier Fe through Magnetic Isolation, washing3O4-
mSiO2-COOH；
S4. carrying precursor medicine GCV
Carboxylated carrier obtained in step S3 is dissolved in the cushioning liquid PBS (15mg/ml, 10ml) of pro-drug GCV
In, stirring is incubated 24h, and magnetic is isolated and purified, and is prepared into the carrier Fe of carrying precursor medicine GCV3O4-mSiO2/GCV；
S5. PLL-g-PEG is prepared
By poly-l-lysine PLL (150000) with polyethylene glycol PEG (100000) in molar ratio for 1: 1 amount mixes,
NHS/EDC reactions are carried out, 25 DEG C of reaction temperature, reaction time 6h forms graft copolymer PLL-g-PEG；
S6. carrier coats PLL-g-PEG
By the carrier of carrying precursor medicine GCV and PLL-g-PEG in mass ratio 2.5 obtained in step S5 obtained in step S4
: 1 mixing, add PBS, pH=7.2,25 DEG C of reaction time 32h of reaction temperature, reaction solution to be done through centrifugation, washing, vacuum
It is dry, the carrier of cladding PLL-g-PEG, i.e. Fe is obtained3O4-mSiO2/GCV@PLL-g-PEG；
S7. TK plasmids are loaded
The carrier of PLL-g-PEG will be coated obtained in S6 with the plasmid of suicide gene TK according to mass ratio 15: 1, PBS is added
Buffer solution, pH=7.2,25 DEG C of reaction temperature, reaction time 32h, reaction solution is obtained complex treatment liver cancer medicine through centrifugation, washing
Thing, i.e. Fe3O4-mSiO2/GCV@PLL-g-PEG/TK。
Experimental example
Physicochemical property, external load medicine and drug release, the property of gene protection for the nanometer medicine-carried system of checking present invention synthesis
Can, and in the validity and security that target Journal of Sex Research, complex treatment liver cancer of cellular level, synthesize using in embodiment 1
Fe3O4-mSiO2/ GCV@PLL-g-PEG/TK carry out following test：
The physicochemical property of the nanometer medicine-carried system of test case 1, external load medicine and drug release, the performance of gene protection
(1) physicochemical property identification
It is bent by nuclear-magnetism, mass spectrum, infrared, dynamic light scattering, sepectrophotofluorometer, transmission electron microscope, nitrogen adsorption-desorption
Line, hysteresis curve characterize its molecular structure, magnetic property and physiological environment to the size of nanometer medicine-carried system, decentralization and knot
The influence of structure stability.Result such as Fig. 1,2,3 institute are not：
Wherein, Fig. 1 is the transmission electron microscope picture of the magnetic-mesoporous silicon dioxide nano rod of nanometer medicine-carried system；Fig. 2 is carried for nanometer
Nitrogen adsorption-the desorption curve of the magnetic-mesoporous silicon dioxide nano rod of medicine body system.Fig. 3 is the magnetic-mesoporous two of nanometer medicine-carried system
Aoxidize the hysteresis curve of silicon nanorod.
(2) it is external to carry medicine inspection survey
Take a certain amount of carboxylated carrier Fe3O4-mSiO2- COOH mixes with the solution containing GCV, 25 DEG C of stirring 24h, centrifugation
After collect supernatant.The content of supernatant GCV is detected by HPLC, Fe is calculated3O4-mSiO2The carrying drug ratio of-COOH is
24% and envelop rate 80%.
(3) external realizing controlled-release medicine inspection is surveyed
By the nanometer medicine-carried system Fe of the above-mentioned preparations of 10mg3O4-mSiO2/ GCV@PLL-g-PEG/TK are scattered in deionization
Water, is fitted into bag filter, is then placed in stirring dialysis in the PBS of pH=5.5 or 7.4.The temperature of buffer solution is
25℃.Taking a small amount of cushioning liquid carries out HPLC detections, determines 0h, 1h, 2h, 4h, 6h, 9h, 12h, 24h, 36h, 48h, 72h, 96h
GCV concentration in above-mentioned different pH buffer, the relation of research GCV and TK gene drug releases, as a result as shown in figure 4, result
Show that medicine release rate under acid condition (pH=5.5) is about 60% in 96 hours, and released under neutrallty condition (pH=7.4)
Rate is put less than 10%, the drugloading rate of the carrier is 24%.
The cellular level nanometer medicine-carried system of test case 2 treats the Effect study of liver cancer
Human liver cancer cell HepG2 in exponential phase is inoculated in 96 orifice plates respectively by 5000 cells/wells, when thin
When intracellular growth reaches 70~80% fusion, it is grouped as follows：
①Fe3O4-mSiO2/ GCV@PLL-g-PEG/TK groups (MSN/GCV/TK)
②Fe3O4-mSiO2/ GCV@PLL-g-PEG/TK+ alternating magnetic field groups (M+MSN/GCV/TK)
③Fe3O4-mSiO2@PLL-g-PEG/TK groups (MSN/TK)
④Fe3O4-mSiO2@PLL-g-PEG/TK+ alternating magnetic field groups (M+MSN/TK)
⑤Fe3O4-mSiO2@PLL-g-PEG/TK+ genetic contrast groups
⑥Fe3O4-mSiO2/ GCV@PLL-g-PEG+ genetic contrast groups
⑦Fe3O4-mSiO2@PLL-g-PEG+ vehicle Controls group (MSN)
8. alternating magnetic field group
9. GCV control groups
Totally 8 groups, every group of 6 multiple holes.Alternating magnetic field group acts on 30min under alternating magnetic field, and each group continues and cell after dosing
After being incubated 48h altogether, mtt assay determines cell survival rate, calculates each group IC50 values.Result is as shown in Figure 5.
The imaging of the integral level nanometer medicine-carried system complex treatment liver cancer of test case 3, validity and security
(1) foundation and administration of Nu/nu mouse-people's HepG2 lotus knurl models
The inoculation human HepG2 cell's strain of Nu/nu BAlB/c mouse backs, treats that tumor size is 60mm~100mm3When start
Administration, is grouped as follows：
①Fe3O4-mSiO2/ GCV@PLL-g-PEG/TK groups (MSN/TK/GCV)
②Fe3O4-mSiO2/ GCV@PLL-g-PEG/TK+ alternating magnetic fields group (AMF+MSN/TK/GCV)
③Fe3O4-mSiO2/ GCV@PLL-g-PEG/TK+ alternating magnetic fields group+magnetic field (M+AMF+MSN/TK/GCV)
④Fe3O4-mSiO2@PLL-g-PEG vehicle Controls group (MSN)
5. GCV control groups (GCV)
6. alternating magnetic field group (AMF)
7. PBS control group (PBS)
Every group of 10 animals, are administered 4 times in d1, d5, d9, d13 tail vein, plus alternating magnetic field group is put into after administration every time
Tumour magnetic nanometer thermotherapy alternating magnetic field occurs in instrument, and heat up 20min in alternating magnetic field.30d puts to death animal, by swollen
Knurl growth volume curve, tumor weight calculate different group tumour inhibiting rates.Result is shown in Fig. 6, and the nanometer passes through the magnetic-meso-porous titanium dioxide
Silicon nanorod and suicide gene/prodrugs therapy method are effectively combined, and can farthest suppress tumour cell, reach treatment
The effect of liver cancer.
(2) NMR imaging technical monitoring therapeutic effect
D0, d1, d5, d9, d13, d20, d27, d34 time point are chosen, with ketamine and xylazine compound anesthetic fiber crops
Liquor-saturated mouse.Using 1.5T magnetic resonance imagers, the multi-functional small coil of wrist joint, FSE (FSE) sequence, T1WI are selected
(TR 400ms, TE11ms), T2WI (R 2000ms, TE91ms), thick-layer 2mm, the number of plies 7, the visual field (FOV) 60mm, matrix 256 ×
224.Liver transplant knurl size is observed using nuclear-magnetism cross section, tumour maximum diameter (a) and therewith minimum in vertical direction is measured
Footpath (b), by formula V=0.52 × a × b2Calculate gross tumor volume, every group of effect for the treatment of liver cancer of Real-Time Evaluation.Result is shown in Fig. 7,
The nanometer is effectively combined by the magnetic-mesoporous silicon dioxide nano rod and suicide gene/prodrugs therapy method, can be killed swollen
Oncocyte, reaches the effect for the treatment of liver cancer.
(3) safety evaluatio of nanometer medicine-carried system
Using nude mice used in method (2), animal is put to death respectively in administration d1, d13, d34, take nude mice liver,spleen,kidney,
The Main Tissues such as lung, the heart and tumour, the change of observation important organ tectology, detection liver function and kidney work(zymetology are dyeed by HE
Index (ALT, AST, BUN, CRE) and hematological indices (WBC, RBC, PLT, PT, APTT, CT) evaluate the safety of nano-carrier
Property.Test proves, the nanometer medicine-carried system has good biocompatibility, relatively low cell toxicant, compared with high saturation and magnetic intensity, can
Suicide gene and pro-drug transmission uniformity temporally and spatially, accurately to release the drug, by the magnetic-meso-porous titanium dioxide
Silicon nanorod and suicide gene/prodrugs therapy method are effectively combined, and improve the combined therapy effect of liver cancer.
Obviously, above-described embodiment is only intended to clearly illustrate example, and not to the restriction of implementation method.It is right
For those of ordinary skill in the art, can also make on the basis of the above description other multi-forms change or
Change.There is no need and unable to be exhaustive to all of implementation method.And the obvious change thus extended out or
Among changing still in the protection domain of the invention.
Claims (10)
1. a kind of nanometer medicine-carried system, it is characterised in that including：Magnetic-mesoporous silicon dioxide nano rod carrier, is supported on the load
Prodrug ganciclovir (GCV) on body, and be total to by the grafting that poly-l-lysine (PLL), polyethylene glycol (PEG) are formed
Polymers PLL-g-PEG, wherein, the PLL-g-PEG has been also loaded suicide gene herpes simplex virus thymidine kinase (TK).
2. nanometer medicine-carried system according to claim 1, it is characterised in that the magnetic-mesoporous silicon dioxide nano rod is carried
Body is embedded with the mesoporous silicon dioxide nano rod of magnetic particle for one end.
3. nanometer medicine-carried system according to claim 1 and 2, it is characterised in that the mesoporous silicon dioxide nano rod
Length is 20-500nm, and a diameter of 70-150nm, aperture is 1-5nm；The particle diameter of the magnetic particle is 50-150nm, specific surface
Product is 400-1200m2/ g, adds up pore volume and is not less than 0.5cm3/g；The magnetic-mesoporous silicon dioxide nano rod carrier magnetic response
Ability is not less than 57emu/g；The GCV load capacity of the mesoporous silicon dioxide nano rod is 5-40%；The suicide gene TK bears
Carrying capacity is 5-20%.
4. the nanometer medicine-carried system according to claim any one of 1-3, it is characterised in that the magnetic particle is r-
Fe2O3、MeFe2O3、Fe3O4, at least one in MnO, NiO, NiFe, FeCo, NiFe, wherein, Me is in Co, Mn, Ni
Kind.
5. a kind of method for preparing the nanometer medicine-carried system described in claim any one of 1-4, it is characterised in that including following step
Suddenly：
(1) functionalization of magnetic-mesoporous silicon dioxide nano rod carrier
Magnetic-mesoporous silicon dioxide nano rod carrier is dissolved in ethanol, silane coupler, reaction solution 105 are added after ultrasonic disperse
Flow back 4h at a temperature of DEG C, separates, washs, dries, and prepares amidized magnetic-mesoporous silicon dioxide nano rod carrier；By institute
State amidized magnetic-mesoporous silicon dioxide nano rod carrier to be added in the succinic anhydride solution of 10-50mg/ml, 25 DEG C of stirrings
24h, product is prepared into carboxylated carrier through Magnetic Isolation, washing；
(2) carrying precursor medicine GCV
The carboxylated carrier prepared by the step (1) is dissolved in the cushioning liquid of pro-drug GCV, stirring is incubated
24h, magnetic is isolated and purified, and is prepared into the carrier of carrying precursor medicine GCV；
(3) PLL-g-PEG is prepared
Poly-l-lysine PLL is carried out into NHS/EDC reactions, reaction temperature with polyethylene glycol PEG in molar ratio for mix at 1: 1
25 DEG C, reaction time 6h forms graft copolymer PLL-g-PEG；
(4) carrier cladding PLL-g-PEG
By the carrier and PLL-g-PEG obtained in the step (3) of the carrying precursor medicine GCV obtained in the step (2)
In mass ratio (1.5-2.5): 1 mixes in physiological conditions, the reaction time is 18-32h, and reaction solution is done through centrifugation, washing, vacuum
It is dry, the carrier of cladding PLL-g-PEG is obtained；
(5) TK plasmids are loaded
By the plasmid of the carrier of the cladding PLL-g-PEG obtained in the step (4) and the suicide gene TK in mass ratio
(5-15): 1 in physiological conditions stirring reaction 18-32h be combined, reaction solution is obtained nano drug-carrying body through centrifugation, washing
System, i.e. Fe3O4-mSiO2/GCV@PLL-g-PEG/TK。
6. the preparation method of a kind of nanometer medicine-carried system according to claim 5, it is characterised in that the poly L- relies ammonia
Acid molecule amount is 70000-150000, and the molecular weight polyethylene glycol is 1000-100000.
7. a kind of preparation method of the nanometer medicine-carried system according to claim 5 or 6, it is characterised in that the step (4)
It is PBS with the physiological condition described in the step (5), pH value is 6.8-7.2, and temperature is 20-25 DEG C.
8. the preparation method of a kind of nanometer medicine-carried system according to claim any one of 5-7, it is characterised in that also include
Following steps：
Prepare magnetic particle
The mixture of magnetic presoma, polyacrylic acid PAA and diethylene glycol (DEG) DEG is stirred 30 points for 30-40 DEG C under nitrogen protection
Clock, 100~1000rpm of speed of agitator is heated to 240~280 DEG C afterwards, continues 100~1000rpm and stirs 30 minutes, is obtained
First reaction solution；
The diethylene glycol (DEG) DEG solution of 60~75 DEG C of NaOH is injected in first reaction solution, is continued 100~1000rpm and is stirred
Reaction in 1 hour is mixed, magnetic particle is generated；
The magnetic particle is separated, is washed, being dried；
Prepare magnetic-mesoporous silicon dioxide nano rod carrier
1ml concentration is added to the aqueous solution of 5-10mg/ml surfactants for the magnetic particle aqueous solution of 8.6mg/ml
In, it is fully dispersed, alkalescent reagent is added, continue to stir 30 minutes after tetraethyl orthosilicate is slowly added to afterwards, wash away the table
Face activating agent, is obtained the magnetic-mesoporous silicon dioxide nano rod carrier.
9. a kind of preparation method of the nanometer medicine-carried system according to claim any one of 5-8, it is characterised in that the magnetic
Property presoma be soluble ferric iron salt, manganese salt, nickel salt in one kind；The polyacrylic acid molecular weight is 1800-15000；The table
Face activating agent is one or more in alkyl quaternary ammonium salts, polyvinylpyrrolidone, polyethyene diamine.
10. a kind of composition, a kind of nanometer medicine-carried system described in its claim any one of 1-4 for including effective therapeutic dose,
And the auxiliary material for pharmaceutically receiving.
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| CN110118816A (en) * | 2018-02-05 | 2019-08-13 | 中国科学院化学研究所 | The method for detecting the bio distribution of nano medicament carrying system in vivo |
| CN109970957A (en) * | 2019-01-23 | 2019-07-05 | 北京诺康达医药科技股份有限公司 | A kind of copolymer of the controllable biodegradable with alkaline copolymerization center |
| CN109970957B (en) * | 2019-01-23 | 2022-04-12 | 北京诺康达医药科技股份有限公司 | Controllable biodegradable copolymer with alkaline copolymerization center |
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